The Synthesis Of (S)-2-aminomethyl-1-ethylpyrrolidine And2,4-diamino-6-(bromomethyl) Pteridine

Part1:(S)-2-Aminomethyl-1-ethylpyrrolidine is an important chiralpharmaceutical intermediate and widely used in the synthesis of antipsychotic drugsof L-sulpiride, sultopride, etc. Consequently, the synthesis of(S)-2-aminomethyl-1-ethylpyrrolidine is valuable.In this paper, we developed a method to prepare (S)-2-aminomethyl-1-ethylpyrrolidine using L-proline as the starting material through N,O-diethylation,ammonolysis, and reduction steps. In order to increase the rate of ammonolysis andreduce the reaction time, the ammonolysis reagent was changed, the catalyst wasadded and the reaction temperature was increased. In the reduction of(S)-1-ethyl-2-pyrrolidinecarboxamide, several reduction systems have been tried andwe found that KBH4-BF3·Et2O was the better one. It owns the advantages of low cost,high yield, and safe operation.All the reactants are easy to obtain and economically inexpensive. This methodhas the advantages of low cost, high yield (total yield:68.6%), simple and safeoperation. This mehod is suitable for chemical industry production.Part2:2,4-Diamino-6-(bromomethyl)pteridine is an important intermediate forthe synthesis of methotrexate and its derivatives which were commonly used asanticancer drugs. Currently, the reported methods for the synthesis of2,4-diamino-6-(bromomethyl)pteridine have some drawbacks, such as low yield,uncommon starting material. Thus, it is valuable to optimize the synthesis of2,4-diamino-6-(bromomethyl)pteridine.In this paper, we use2,4,5,6-tetraaminopyrimidine and1,3-dihydroxyacetone asthe starting materials,2,4-diamino-6-(hydroxymethyl)pteridine was obtained after thecyclization. Then2,4-diamino-6-(bromomethyl)pteridine was generated bybromization of2,4-diamino-6-(hydroxymethyl)pteridine. In order to improve the yield,the synthetic route was optimized. The total yield is38.3%.This method was simple in operation, and the starting materials were inexpensiveand commercially available, so it was suitable for industrial production of2,4-diamino-6-(bromomethyl)pteridine.